POS1608 MIRNA BIOMARKERS FOR ARTICULAR AND CUTANEOUS RESPONSE TO METHOTREXATE IN PSORIATIC ARTHRITIS
Authors: O. Cruz Correa, D. Ganatra, A. Garrido, R. Machhar, S. Lively, M. Kapoor, D. D. Gladman
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Psoriatic arthritis (PsA) is a chronic, progressive disease associated with psoriasis that can lead to joint damage, disability, and increased mortality. Early diagnosis and management of inflammation is essential for improving clinical outcomes. Methotrexate (MTX) is the recommended first-line treatment for early PsA patients with polyarthritis and relevant skin involvement, however many patients are unresponsive to therapy. MicroRNA (miRNA) modulate gene expression at a post-transcriptional level and constitute a promising source of biomarkers that could enable the future personalization of treatment plans. <h3>Objectives</h3> To identify a set of miRNAs that serve as biomarkers for MTX treatment response by comparing miRNA expression between responders and non-responders before initiation of therapy. <h3>Methods</h3> From our prospective PsA database we identified biologic-naive PsA patients satisfying the CASPAR criteria before the initiation and 6 months after MTX treatment. Articular response to MTX was defined as achieving a treatment target of low disease activity (4 ≤ DAPSA &lt; 14) or remission (DAPSA &lt; 4). Cutaneous response to MTX was defined as a reduction of at least 50% in PASI score. miRNA expression was evaluated in biobanked serum samples through next-generation sequencing. Differential expression was assessed by linear modelling with empirical Bayes moderation (using the Limma R package). Linear models were corrected for sequencing batch, age, sex, ethnicity, BMI, smoking, use of NSAIDs, MTX treatment duration and dose. Enrichment of biologic pathways corresponding to gene targets of the identified miRNAs was examined using the integrative tool pathDIP by restricting the analysis to literature curated pathways and experimentally detected protein-protein interactions with a prediction confidence of 0.99. <h3>Results</h3> 70 biologic-naive, PsA patients were included in the study. Articular and cutaneous response to MTX was observed in 28.57% and 34.28% of patients, respectively. Pretreatment expression of miR-127-3p was significantly lower in patients showing an articular response to MTX (p&lt;0.001). Of note, miRNA 127 expression has been associated with a protective effect in inflammatory lung fibrosis and osteoarthritis[1]. A set of 7 miRNAs (miR-155-5p, miR-140-3p, miR-432-5p, miR-382-5p, miR-532-5p, miR-139-3p, and miR-379-5p) were significantly associated (p&lt;0.01) with cutaneous response to MTX. The most commonly enriched signaling pathway targeted by these miRNAs is the PI3K/AKT/mTOR which is a key regulator of keratinocyte proliferation[2]. <h3>Conclusion</h3> We identified miR-127-3p as a biomarker of articular response, and 7 other miRNAs as biomarkers of cutaneous response to MTX treatment in PsA patients. <h3>References</h3> [1]Dong J, Li L, Fang X, Zang M. Exosome-Encapsulated microRNA-127-3p Released from Bone Marrow-Derived Mesenchymal Stem Cells Alleviates Osteoarthritis Through Regulating CDH11-Mediated Wnt/β-Catenin Pathway. J Pain Res. 2021 Feb 4;14:297-310. [2]Zhang M, Zhang X. The role of PI3K/AKT/FOXO signaling in psoriasis. Arch Dermatol Res. 2019 Mar;311(2):83-91. <h3>Acknowledgements</h3> We thank Pratibha Potla for technical help with the bioinformatics analysis. Omar Cruz Correa is supported by awards from the National Psoriasis Foundation (Early Career Grant 815779) and Arthritis Society (Postdoctoral Award 20-0000000015). Rohan Machhar conducted the work prior to any industry affiliation. The Research Program and sequencing experiments are supported by the Canadian Institutes of Health Research, the Krembil Foundation, the Schroder Arthritis Institute and the UHN Foundation. <h3>Disclosure of Interests</h3> None Declared.